NR4A1-mediated regulation of immune evasion in lymphoma

Tumour cells have developed a number of mechanisms to avoid or suppress their recognition, targeting and killing by immune cells. We found out that a part of aggressive B cell lymphomas, a tumour consisting of the antibody-producing cells, exhibited low expression of the transcription factor NR4A1. NR4A1, like other transcription factors, regulates numerous biological processes in cells. However, its function has not been yet investigated in aggressive B cell lymphomas. In our preliminary study, we observed that low NR4A1 level was associated with reduced survival in patients treated with standard therapy. In mice with a functional immune system, we showed that loss of Nr4a1 markedly accelerated the development of lymphoma, with increased presence of surface molecules that inhibit immune cells, but also a higher content of these immune cells compared to immune deficient mouse models. Further, our analyses indicate that loss of Nr4a1 is linked to reduced killing of lymphoma by immune cells. Taken together our data indicate a tumour-suppressive function of NR4A1 mediated by its immune regulatory properties in the development of aggressive lymphomas. In the planned project, we aim to elucidate which genes and/or genetic programs are regulated by NR4A1 with global genetic approaches and to investigate the impact of NR4A1 on immune cell composition and activity in aggressive lymphomas using novel sequencing technologies. In addition, our aim is to functionally test the efficacy of immune therapies as single agents as well as in combination (including novel molecules) in relation to the NR4A1 level in aggressive lymphomas. Finally, we will transfer data from the preclinical model to patients samples and investigate NR4A1 expression, antigen presentation, and immune suppressive surface molecules in our DLBCL patient cohort to validate our findings in a more clinical setting. Based on the finding, we might identify a novel mechanism, which significantly contribute to lymphoma development and which can be used to identify lymphoma patients who may benefit from a novel type of immune therapy.